This proposal aims to establish whether opioids control the effect of chemokines on central neurons and to identify the cellular and molecular mechanisms involved. Functional and physical interactions between opioids, chemokines and their receptors will be investigated, focusing on the modulatory action of mu-opioid agonists on neuronal responses to the chemokine CXCL12 (SDF-1), the natural CXCR4 ligand. The proposed experiments will test the hypothesis that opioids regulate the neuronal actions of CXCL12 (mainly the activation of intracellular pathways involved in neuronal survival) and that this may contribute to the deleterious effects of CXCR4 under pathological conditions, such as neuroAIDS. The first Specific Aim will provide insights into the mechanisms whereby opioids interfere with recruitment of neuronal survival pathways by CXCR4 in cultured neurons. The goal of these experiments is to establish whether the primary target of opioid action is CXCR4 or its downstream signaling pathways. The studies proposed in the second Specific Aim will focus on the kinetics of the opioids action on CXCR4 and determine whether continued exposure to mu-agonists is required to inhibit CXCL12-induced responses;also these experiments will study the effects of in vitro and in vivo morphine treatments. This information will better characterize the action of opioids on CXCL12 and help us evaluate the potential pathological implications of such regulation, which will be further exploited in the third aim. This last Specific Aim will evaluate the role of mu-opioid agonists in the context of HIV neuropathology and focus on the effect of mu-opioid receptor activation on HIV neurotoxicity. Well-established in vitro and ex vivo techniques of cellular and molecular pharmacology will be employed, along with more novel molecular biology and imaging approaches. The long-term goal of the proposed studies is to characterize the cellular and environmental factors that regulate the action of chemokines on neurons, which will lead to a better understanding of the physiological and pathological role of chemokines in the CNS. Furthermore, as progression to neuroAIDS appears more dramatic in patients with history of drug abuse, these studies may also reveal unknown correlations between opioids and chemokines that might be useful to the clinical management and therapy of HIV-infected drug abusers.